Throughout this application, various publications are referenced in parentheses. Full citations for these publications may be found listed at the end of the specification. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein.
Recurrent chromosomal translocations recognized in the majority of lymphomas provide clues to mechanisms of lymphomagenesis. Immunoglobulin genes undergo specific rearrangements during differentiation of lymphoid cells and, errors in recombination lead to chromosome translocation and neoplastic transformation (Chaganti, R. S. K., 1991; Rabbits, T. H., 1994). Diffuse large cell lymphomas (DLCL) make up approximately 50% of non-Hodgkin lymphomas (Simon, R., et al., 1988) and show significant variability in terms of their pathologic manifestation, response to therapy and prognosis (Magrath, I., 1989). DLCL are also highly heterogeneous with respect to karyotypic abnormalities as well as underlying molecular lesions. So far, three genes have been identified whose normal pattern of expression is altered by a specific chromosomal translocation in DLCL, namely, MYC, BCL2 and BCL6, occurring in approximately 10%, 20% and 25% of DLCL respectively, as detected by either cytogenetic or molecular methods (Chaganti, R. S. K., et al., 1991; Rabbits, T. H., 1994; Ladanyi, M., 1991; Offit, K., 1991; Offit, K., 1994). The remaining DLCL exhibit a number of small subsets each characterized by a specific site of recurrent chromosomal rearrangement. The molecular genetic analysis of these sites can contribute significantly to our understanding of the mechanisms of B-cell lymphomagenesis.
One of the recurrent sites of rearrangement seen in 3-4% of DLCL cases is 15q11-13. A notable feature of this site is promiscuity of rearrangement. In addition to translocations involving the immunoglobulin gene sites 14q32 and 22q11, it exhibits translocations with multiple other sites, such as 9p13, 1p32, 7p13, 12q24 and 15q22. Translocations involving 15q11-13 have also been noted in non-lymphoid tumors (Mittelman, F., 1994). The 15q11-13 region has been implicated in genomic imprinting and contains putative genes for human imprinting related disorders such as Prader-Willi and Angelman syndromes. Another unusual feature of the region is the presence of orphan, presumably non-functional, copies of V and D segments of the immunoglobulin heavy chain gene (Tomlinson, I. M., et al., 1994; Wintle, R. F., 1994). The cloning of the t(14:15)(q32;q11-13) breakpoint from a DLCL case and the isolation of a new gene, here named, bcl-8 located at 15q11-13 and potentially involved in the pathogenesis of DLCL is reported.